TY - JOUR
T1 - Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma
AU - Tjin, Esther P M
AU - Groen, Richard W J
AU - Vogelzang, Irma
AU - Derksen, Patrick W B
AU - Klok, Melanie D
AU - Meijer, Helen P
AU - van Eeden, Susanne
AU - Pals, Steven T
AU - Spaargaren, Marcel
PY - 2006/1/15
Y1 - 2006/1/15
N2 - Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.
AB - Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.
KW - 3-Phosphoinositide-Dependent Protein Kinases
KW - Cell Adhesion
KW - Class I Phosphatidylinositol 3-Kinases
KW - Forkhead Box Protein O3
KW - Forkhead Transcription Factors/metabolism
KW - Germ-Line Mutation
KW - Glycogen Synthase Kinase 3/metabolism
KW - Hepatocyte Growth Factor/genetics
KW - Humans
KW - In Situ Hybridization
KW - Lymphoma, B-Cell/genetics
KW - Lymphoma, Large B-Cell, Diffuse/genetics
KW - MAP Kinase Kinase 1/metabolism
KW - Macrophages
KW - Mitogen-Activated Protein Kinase 1/metabolism
KW - Mitogen-Activated Protein Kinase 3/metabolism
KW - Multiple Myeloma/genetics
KW - Mutation, Missense
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Phosphorylation
KW - Polymerase Chain Reaction
KW - Polymorphism, Single-Stranded Conformational
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Proto-Oncogene Proteins/metabolism
KW - Proto-Oncogene Proteins c-met
KW - RNA Probes
KW - RNA, Messenger
KW - Receptors, Growth Factor/metabolism
KW - Serine Endopeptidases/metabolism
KW - Signal Transduction
KW - Tumor Cells, Cultured
U2 - 10.1182/blood-2005-05-1929
DO - 10.1182/blood-2005-05-1929
M3 - Article
C2 - 16189274
VL - 107
SP - 760
EP - 768
JO - Blood
JF - Blood
SN - 0006-4971
IS - 2
ER -